Project Summary This project investigates the neurobiological mechanisms of sensory symptoms in patients with obsessive- compulsive disorder (OCD) and their unaffected siblings using task-based fMRI, resting-state functional connectivity, and diffusion MRI approaches. OCD is a chronic disorder presenting a high public health burden. Treatment presents a particular challenge because OCD is extremely heterogeneous, with clusters of symptoms likely derived from differing neural etiologies. The Research Domain Criteria (RDoC) approach seeks to address this problem by investigating dimensional components of behavior that more closely align with brain circuitry. This application focuses on the dimensional symptom of sensory phenomena (SP), which are uncomfortable or aversive sensory experiences that drive repetitive behaviors in OCD, including ?not just right? sensations, physical urges, and sensations of disgust. SP are very prevalent, occurring in 60-80% of OCD patients, and experienced as highly distressing. Unfortunately, SP are not well addressed by standard treatment approaches, which may be in part because their neurobiological mechanisms are not well understood. Our preliminary data indicated that severity of SP in OCD patients was associated with activation of the insula, somatosensory cortex, and motor regions ? areas previously associated with the detection of body sensation and physical urges ? during two different fMRI tasks. Furthermore, greater severity of SP was related to greater resting-state functional connectivity between somatosensory regions, insula, and prefrontal cortex. This project builds on these promising preliminary data to (1) investigate the neural mechanisms of SP in a larger OCD cohort showing the full range of SP severity and (2) probe for familial risk markers in unaffected siblings. For Aim 1, SP will be measured in 100 OCD patients using the Sensory Phenomena Scale. Diffusion and fMRI data will be acquired during rest and fMRI tasks previously validated to recruit insula and sensorimotor regions. In order to identify familial risk markers, Aim 2 will compare sensory phenomena and neural circuitry between OCD probands, 50 of their unaffected biological siblings, and 50 unrelated healthy controls without a family history of Axis 1 disorders. Additional analyses will investigate the relationship between neuroimaging measures and other dimensional symptoms relevant for OCD (perseverative thought, harm avoidance, perfectionism), with path analyses testing a model of direct and specific pathways from neuroimaging measures to SP. This proposal investigates a significant and highly prevalent cluster of symptoms whose neurobiology remains elusive. Our use of complementary neuroimaging techniques will comprehensively assess the neural circuitry underlying SP and probe for markers of risk that could be targeted by future treatments.